Abstract: The proposal addresses the poorly explored problem of microglia regulation by neurons. Activation of microglia is at the core of brain homeostasis, where microglia cells are involved in neuronal surveillance, as well as in immune defense against pathogens. We hypothesize that such cellular dynamics that shape brain function in health and disease require microglia tuning to the specific functions of highly specialized neurons in distinct brain areas. Our plans include investigations of spatial microglia diversity and its developmental mechanisms. Using methods of mouse genetics, we will access the possibility of microglia mimicry of its neuronal environment and its role in the regulation of microglia-mediated inflammatory response. In a complementary set of experiments, we will address the role of neuronal activity on microglia function and inflammatory gene activation. Our proposal has far reaching consequences for understanding of the role of microglia-neuron interaction in the regulation of inflammatory responses in the brain. The proposed work establishes deep connections between the disparate fields of neuroscience, cell differentiation, lineage plasticity and innate immunity. Thus, it will generate a new framework for understanding of the microglia-neuron interaction with fundamental implications for how we understand and control microglia function, especially within the context of neurodegenerative diseases. Public Health Relevance: The proposed research addresses a poorly understood mechanism of microglia -neuron interaction and its role in microglia-mediated inflammatory responses. Beyond the fundamental basic science implications, our work has the potential of revolutionizing strategies to study the mechanisms of neurodegeneration and its treatment. Our findings will provide a foundation for the development of new approaches for treatment of inflammation associated neurodegenerative disease such as Parkinson's, Huntington's, and Alzheimer disease.